Combinations of carbidopa and levodopa to treat Parkinson's disease are known in the pharmaceutical arts. Several products currently on the North American market, including SINEMET® (Merck Co.) and SINEMET® (Merck Co.) CR contain combinations of carbidopa and levodopa in immediate release and controlled release forms, respectively. Overseas, other decarboxylase inhibitor and levodopa combinations include those sold under the mark Madopark (levodopa with benserizide instead of carbidopa).
The carbidopa and levodopa combination is used to treat the symptoms of Parkinson's disease, which is characterized by abnormally low levels of dopamine. Dopamine is a neurotransmitter having significant influence over the mobility and control of the skeletal muscular system. Patients suffering from Parkinson's disease frequently have periods in which their mobility becomes difficult, often resulting in an inability to move.
Administering dopamine is not effective to treat Parkinson's disease because dopamine does not cross the blood brain barrier. To resolve this failure, Parkinson's patients are administered levodopa, the metabolic precursor of dopamine. Levodopa crosses the blood brain barrier and is rapidly converted to dopamine, thereby alleviating the symptoms of Parkinson's disease caused by reduced levels of dopamine. Levodopa is problematic because of its rapid decarboxylation by tissues other than the brain. Thus, when levodopa is administered alone, large doses are required because only a small portion is transported to the brain unchanged.
Patients treated with levodopa therapy for Parkinson's disease may frequently develop motor fluctuations characterized by end-of-dose failure, peak dose dyskinesia and akinesia. An advanced form of motor fluctuations is known as the “on-off effect” in which the patient suffers from unpredictable swings from mobility to immobility. It is believed that the on-off effect can be minimized in some patients with a treatment regimen which produces narrow ranges of plasma levels of levodopa.
Carbidopa inhibits the decarboxylation of levodopa by a patient's body tissues outside of the brain. Small doses of carbidopa administered in conjunction with levodopa allow a larger percentage of levodopa to reach the brain unchanged for later conversion to dopamine. There is at least one study reporting that carbidopa reduces the amount of levodopa required to produce a given response by about 75% and, when administered in conjunction with levodopa, increases plasma levels and the plasma half life of levodopa. The carbidopa and levodopa combination allows for lower doses of levodopa with a concordant reduction of side effects.
The carbidopa and levodopa combination is now available in immediate release as well as controlled release compositions. The controlled release formulations allow for the continuous release of drug over a prolonged period in an attempt to maintain tight levodopa plasma ranges. However, the use of controlled release dosage forms are problematic in that many Parkinson's patients wake up in the morning having little or no mobility due to the wearing off of the previous dose taken the day or evening before. Once the previous dose has worn off, such patients are usually unwilling or unable to wait for the extended period of time required for a controlled release dosage form to deliver the appropriate plasma levels of levodopa. The use of immediate release formulations require more frequent dosing and are associated with more fluctuating plasma levodopa concentrations.
Combination immediate release and controlled release carbidopa and levodopa dosage forms are described in U.S. Pat. No. 6,238,699 to Rubin, entitled Pharmaceutical Formulations Containing A Combination Of Carbidopa And Levodopa, issued May 29, 2001, which discloses an immediate release and controlled release carbidopa and levodopa combination product, and is incorporated herein by reference.
There remains, however, a continuing need for immediate release and controlled release carbidopa and levodopa products which will improve the administration of levodopa to Parkinson's patients by narrowing blood plasma ranges of levodopa and reducing side effects.